Brain Cell-Type Specific Enhancer-Promoter Interactions and Disease Risk
Post by Stephanie Williams
What's the science?
The relationship between common genetic variation, regulatory elements in different types of brain cells, and disease risk is poorly characterized. Regulatory elements, such as promoters and enhancers, which control the expression of genes, vary across cell types. It is possible that particular common genetic variants (i.e. single nucleotide polymorphisms) that confer disease risk, may also interact with cell-type-specific regulatory elements to affect the risk of psychiatric and neurological diseases. This week in Science, Nott, and colleagues analyzed the regulatory elements of four major cell types in the brain to establish cell-type specific enhancer-promoter maps and to understand the relationship between regulatory elements and disease risk across different cells.
How did they do it?
First, the authors performed a series of analyses to characterize the regulatory regions for four major cell types in the human brain. They extracted their samples from post-mortem cortical tissue from six individuals. They group cells into four major types, including neuronal cells and three types of non-neuronal cells, including microglia, oligodendrocytes, and astrocytes. The authors identified active promoters and enhancers in each cell type in order to establish enhancer-promoter maps. The authors then used statistics from previous genome-wide association studies (GWAS) that characterized different risk alleles (common genetic variants conferring risk) for neurological disorders, psychiatric disorders, and neurobehavioral traits to investigate how risk variants were related to the identified regulatory elements. They used the results from these analyses to further probe the relationship between particular disease risk variants (eg. Alzheimer’s risk variants) and regulatory elements within specific sets of cells (eg. microglia). The authors selected a subset of previously-defined Alzheimer’s risk variants and analyzed whether those variants overlapped with cell-type-specific regulatory elements that they had identified. They performed a series of steps to confirm that those genomic regions containing the risk variants interacted with active promoters. These steps resulted in 41 genes that spanned all 4 cell types, which were linked to the variants. Of the 41 genes, 25 were identified in microglia, and the remaining were not identified in the other types of cells that the authors looked at. They then repeated this analysis with other Alzheimer’s disease genome-wide association studies and found a greater number of risk genes. They focus on one particular enhancer that contains an Alzheimer’s Disease risk variant with the second highest Alzheimer’s Disease risk score. They performed analyses to verify the functionality of the enhancer and to investigate the cell-type specificity of the enhancer.
What did they find?
When the authors analyzed which regulatory elements were active in the nuclei of their different cell types, they found that their data clustered according to cell type and showed cell-type-specific patterns. They found that the promoters associated with cell-type-specific signatures exhibited specific H3K27ac (a type of histone modification) profiles. From their analysis on the relationship between promoters and enhancers, the authors found that there was a large amount of overlap in the active promoters across different cell types, while there was very little overlap in the active enhancers across cell types. They suggest that the cell-type specificity is therefore captured by the group of active enhancers. From their analysis on the relationship between the regulatory regions of their four classes of cells and complex traits and diseases, the authors found that 1) psychiatric disorders and behavioral trait heritability was most highly enriched for enhancers and promoters in neuronal cells, and 2) Alzheimer’s heritability was most highly enriched in microglia-specific regulatory regions. In particular, the authors showed that Alzheimer’s heritability was enhanced in microglial enhancers. Methodologically, results from their analysis on promotors and distal regulatory regions with a technique called proximity ligation-assisted ChIP seq (PLAC), showed that PLAC could be used to identify cell-type-specific promoter-enhancer interactions.
They identified several thousand clusters of multiple enhancers, called super-enhancers, which are thought to be important in driving the expression of cell identity genes. Of the super-enhancers that they identified, many contained GWAS disease-risk variants and were related to cell-type-specific genes. These results suggest that some GWAS variants may act on these clusters of enhancers to affect gene expression. From their series of analyses on Alzheimer’s Disease-risk variants, the authors identified several interesting characteristics of Alzheimer’s Disease variants. They found that the risk variants were usually linked to active promoters that were far away, and not to the closest gene promoter. They also found that although some Alzheimer’s Disease risk variants were expressed in different cell types, there were microglia-specific enhancers that contained the risk variants. The authors focused on the BIN1 (a gene involved in Alzheimer’s risk) enhancer, which contained a risk variant with the second highest AD-risk score after APOE, and confirmed that the risk allele associated with BIN1 was contained in the microglia-specific enhancers.
What's the impact?
The authors collected evidence that advances our understanding of promoter-enhancer interactions in specific cell types and characterized associations between cell-type-specific regulatory elements and particular disease risk variants. They show that risk variants for psychiatric disorders are associated with regulatory elements within neurons, while a particular risk variant for sporadic Alzheimer’s disease is regulated by a microglia-specific enhancer.
Nott et al. Brain cell type-specific enhancer-promoter interactome maps and disease-risk association. Science. (2019). Access the original scientific publication here.